Abstract Pancreatic cancers are devastating diseases with five year survival rate less than 7%. Currently, there is no effective treatment for advanced disease. One major barrier to efficacy of anti-tumor therapeutics is the dense desmoplastic stromal response. Evidence suggests that cancer associated pancreatic stellate cells (CAPaSC) produce the stromal collagen. The ECM laid down by CAPaSC is considered to be one of the major contributors of resistance to established therapies of the diseases. Depleting CAPaSC and altering vessel density could significantly improve efficacy of existing pancreatic ductal adenocarcinoma (PDAC) treatments. However, currently, there are no approved therapies that are able to deplete CAPaSCs in PDAC. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin ?v?3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin ?v?3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of???). We reasoned that, since both CAPaSC and angiogenic endothelial cells express high levels of integrin ?v?3, and since ProAgio is very effective in inducing apoptosis of integrin ?v?3 expressing cells, ProAgio should both deplete CAPaSC and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. This early phase STTR research project aims at testing effectiveness and safety of this newly developed protein drug candidate in treatment of pancreatic cancer in animal models. This research project will provide proof-of-principle evidence for further development of ProAgio as pancreatic cancer treatment drug, an unmet medical needs. The specific aims of this project are: (1) We will examine the anti- tumor efficacy of ProAgio and its effect on the tumor microenvironment in an immune-competent mouse model of PDAC. (2) We will also examine the effects of ProAgio in combination with a FDA approved anti-cancer therapeutics. (3) Finally, to facilitate further development, we will test pre- clinical toxicity and PK properties of ProAgio in rodent. Our goal is that, through our study, we will introduce a new treatment approach for pancreatic cancer with novel mechanism of drug action.